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There are currently no standard first-line treatment options for patients with higher grade 2–3, well-differentiated, advanced, gastroenteropancreatic neuroendocrine tumours. We aimed to investigate the efficacy and safety of first-line [177Lu]Lu-DOTA-TATE (177Lu-Dotatate) treatment. NETTER-2 was an open-label, randomised, parallel-group, superiority, phase 3 trial. We enrolled patients (aged ≥15 years) with newly diagnosed higher grade 2 (Ki67 ≥10% and ≤20%) and grade 3 (Ki67 >20% and ≤55%), somatostatin receptor-positive (in all target lesions), advanced gastroenteropancreatic neuroendocrine tumours from 45 centres across nine countries in North America, Europe, and Asia. We used interactive response technologies to randomly assign (2:1) patients to receive four cycles (cycle interval was 8 weeks ± 1 week) of intravenous 177Lu-Dotatate plus intramuscular octreotide 30 mg long-acting repeatable (LAR) then octreotide 30 mg LAR every 4 weeks (177Lu-Dotatate group) or high-dose octreotide 60 mg LAR every 4 weeks (control group), stratified by neuroendocrine tumour grade (2 vs 3) and origin (pancreas vs other). Tumour assessments were done at baseline, week 16, and week 24, and then every 12 weeks until disease progression or death. The primary endpoint was progression-free survival by blinded, independent, central radiology assessment. We did the primary analysis at 101 progression-free survival events as the final progression-free survival analysis. NETTER-2 is registered with ClinicalTrials.gov, NCT03972488, and is active and not recruiting. Between Jan 22, 2020, and Oct 13, 2022, we screened 261 patients, 35 (13%) of whom were excluded. We randomly assigned 226 (87%) patients (121 [54%] male and 105 [46%] female) to the 177Lu-Dotatate group (n=151 [67%]) and control group (n=75 [33%]). Median progression-free survival was 8·5 months (95% CI 7·7–13·8) in the control group and 22·8 months (19·4–not estimated) in the 177Lu-Dotatate group (stratified hazard ratio 0·276 [0·182–0·418]; p<0·0001). During the treatment period, adverse events (of any grade) occurred in 136 (93%) of 147 treated patients in the 177Lu-Dotatate group and 69 (95%) of 73 treated patients in the control group. There were no study drug-related deaths during the treatment period. First-line 177Lu-Dotatate plus octreotide LAR significantly extended median progression-free survival (by 14 months) in patients with grade 2 or 3 advanced gastroenteropancreatic neuroendocrine tumours. 177Lu-Dotatate should be considered a new standard of care in first-line therapy in this population. Advanced Accelerator Applications, a Novartis Company.

Background Neuroendocrine tumors typically arise from pancreatic (PNET) vs. gastrointestinal or thoracic origins (non-PNET). The impact of primary tumor site on long-term prognosis following resection of neuroendocrine liver metastasis (NELM) remains poorly defined. The objective of the current study was to define the association of primary tumor location on prognosis of patients undergoing curative intent liver resection for NELM. Methods Between 1990 and 2014, 421 patients who underwent resection of NELM were identified from a multi-institutional database. Clinicopathological characteristics, operative details, and outcomes were stratified and analyzed by location of the primary tumor (PNET vs. non-PNET). A propensity score-matched analysis was utilized to assess the impact of primary tumor location on long-term survival. Results Among the 421 patients, 197 (46.8%) patients had NELM from a PNET primary while 224 (53.2%) had a non-PNET primary (small bowel, n  = 145; rectal, n  = 10; bronchial, n  = 22; other, n  = 47). There were no differences in tumor burden and tumor site, while presence of extrahepatic disease was more common among patients with non-PNET NELM (extrahepatic disease, PNET NELM, n  = 11 27.5% vs. non-PNET NELM, n  = 29 72.5%; p  = 0.010). Patients with PNET NELM were more likely to have non-functional disease compared with patients who had non-PNET NELM (non-functional, PNET NELM, n  = 117 54.9% vs. non-PNET NELM, n  = 96 45.1%; p  = 0.011). On the final pathological specimen of the resected NELM, patients with PNET NELM were more likely to have a moderately differentiated tumor (59.3%), while patients with non-PNET NELM were more likely to have a poorly differentiated tumor (67.8%) ( p  = 0.005). Patients with PNET NELM had a worse 5-year DFS and 5-year OS compared with patients who had non-PNET NELM (DFS, PNET 36.2% vs. non-PNET 55.2%; p  = 0.001 and OS, PNET 79.5% vs. non-PNET 83.4%; p  = 0.008). After propensity score matching, both 5-year DFS and 5-year OS of the PNET and non-PNET groups were comparable (DFS, PNET 46.2% vs. non-PNET 55.9%; p  = 0.22 and OS, PNET 81.5% vs. non-PNET 84.3%; p  = 0.19). Conclusion PNET patients more often present with non-functional NELM and moderately differentiated tumors. On propensity-matched analysis, factors such as extrahepatic disease and tumor grade, but not primary tumor location, were associated with prognosis of patients undergoing curative intent liver surgery for NELM.

Several studies have suggested that chemotherapy prolonged survival in patients with metastatic or recurrent small bowel adenocarcinoma (SBA); however, there is still no standard chemotherapy regimen. Here, we evaluated the efficacy and safety of a 5-fluorouracil (5-FU)/L-leucovorin (l-LV)/oxaliplatin (mFOLFOX6) protocol as a first-line therapy for patients with SBA. This was a multicenter, single-arm, open-label phase II study. Eligibility criteria included histologically confirmed adenocarcinoma, age 20–80 years, and an Eastern Cooperative Oncology Group performance status (PS) of 0–2. The primary endpoint was 1-year progression-free survival (PFS). The secondary endpoints included overall response rate (ORR), overall survival (OS), overall PFS, and safety. Between April 2010 and November 2012, 24 patients were enrolled from 12 institutions. The median age of the patients was 63 years (range 31–79) and there was a male/female ratio of 18/6. The number of PS 0/1 patients was 17/7 and locally advanced/metastatic disease was seen in 2/22 patients, respectively. The primary tumor site was the duodenum in 14 patients (58%) and jejunum in 10 patients (42%). The median follow-up time was 14.7 months (3.7–40.3). The 1-year PFS was 23.3%. The ORR was 9/20 (45%). The median PFS and OS times were 5.9 months (95% confidence interval [CI] 3.0–10.2) and 17.3 months (95% CI 11.7–19.0), respectively. Major grade 3/4 toxicities were neutropenia (38%), anemia/peripheral neuropathy (25%), and stenosis (17%). There were no treatment-related deaths. Although the primary endpoint was not met, mFOLFOX6 showed effective and good tolerance as a first-line treatment for SBA.

Background Radioembolization (RE) with intra-arterial administration of 90 Y microspheres is a promising technique for the treatment of liver metastases from small intestinal neuroendocrine tumors (SI-NET) not amenable to surgery or local ablation. However, studies comparing RE to other loco-regional therapies are lacking. The aim of this randomized study was to compare the therapeutic response and safety after RE and bland hepatic arterial embolization (HAE), and to investigate early therapy-induced changes with diffusion-weighted MRI (DWI-MRI). Methods Eleven patients were included in a prospective randomized controlled pilot study, six assigned to RE and five to HAE. Response according to RECIST 1.1 using MRI or CT at 3 and 6 months post-treatment was recorded as well as changes in DWI-MRI parameters after 1 month. Data on biochemical tumor response, toxicity, and side effects were also collected. Results Three months after treatment, all patients in the HAE group showed partial response according to RECIST while none in the RE group did ( p  = 0.0022). After 6 months, the response rates were 4/5 (80%) and 2/6 (33%) in the HAE and RE groups, respectively (NS). DWI-MRI metrics could not predict RECIST response, but lower pretreatment ADC (120–800) and larger ADC (0–800) increase at 1 month were related to larger decrease in tumor diameter when all tumors were counted. Conclusion HAE resulted in significantly higher RECIST response after 3 months, but no difference compared to RE remained after 6 months. These preliminary findings indicate that HAE remains a safe option for the treatment of liver metastases from SI-NET, and further studies are needed to establish the role of RE and the predictive value of MR-DWI.

The objective of the study was to examine diagnosis and outcome in a series of patients with small bowel tumors detected by capsule endoscopy (CE) in three Australian centers. Review of prospectively collected data from 416 CEs identified 27 tumors in 26 patients. Clinical parameters, tumor histology, and follow-up are reported. Twenty-seven tumors were identified in 26 patients (mean age 61 +/- 13.7 yr). Indications for CE were obscure gastrointestinal (GI) bleeding (21), suspected tumor (3), abdominal pain (1), diarrhea (1). Prior radiology found a possible lesion in 8 of 23 (35%). Nine tumors were proven benign: hamartoma (4), cystic lymphangioma (1), primary amyloid (1), lipoma (1). Two lesions were non-neoplastic: heterotopic gastric mucosa and inflammatory fibroid polyp. Seventeen tumors were malignant: five adenocarcinomas, six carcinoids, two melanoma metastases, two gastrointestinal stromal tumors (GIST), one colon carcinoma metastasis, one non-Hodgkin's lymphoma. Tumors were surgically resected in 23 patients. Resection was considered curative in 12 (52%). Mean duration of follow-up was 26 +/- 13.7 months. Of the five patients with primary adenocarcinoma only one remains disease free. Three of the six with carcinoid tumors have had no recurrence up to 51 months postresection. Both patients with GIST are disease free. Anemia resolved after surgery in the patients with melanoma. Small bowel tumors are a significant finding at CE and are often missed by other methods of investigation. In many patients, detection of a tumor alters management and improves outcome. Even in malignant lesions, treatment is potentially curative in the absence of metastatic disease.

First author Martyn Caplin (Royal Free Hospital, London, UK) said, \"The CLARINET study demonstrated not only significant anti-tumour effect of lanreotide autogel in both intestinal and pancreatic NET cohorts but also demonstrated impressive results in patients with grade 2 NETs and in patients who had more than 25% of their liver replaced by tumour metastases.\"

This study aimed to determine whether Helicobacter pylori eradication limits the progression of precancerous changes, manifested as intestinal metaplasia (IM), in patients with reflux esophagitis using long-term esomeprazole. Three hundred twenty-five reflux esophagitis patients were enrolled and randomly assigned to (i) the H. pylori-positive eradication group receiving 1-week triple therapy (n=105); (ii) H. pylori-positive non-eradication controls (n=105); and (iii) H. pylori-negative controls (n=115). All the patients received continuous esomeprazole until sustained symptomatic response, and when possible, shifted to on-demand therapy (ODT) thereafter. Serial gastroscopy was scheduled on enrollment and at the end of the first and second years to assess the prevalence and progression or regression of gastric atrophy (AT) and IM. There were 93 patients in the H. pylori-eradication group, 83 in the non-eradication controls, and 100 in the negative controls to complete the study. The negative controls had no progression of AT and IM during follow-up. For the H. pylori-positive eradication group, there was significant regression of AT and IM during follow-up (P<0.05). In the H. pylori-positive non-treated controls, the prevalence rates of AT and IM were significantly greater on the second year than on enrollment (P<0.05). During the second-year follow-up, the patients in the eradication group achieved more regression and less development of AT and IM than did the non-eradication controls (P<0.001). In patients using long-term esomeprazole for reflux esophagitis, screening for and eradicating H. pylori infection are necessary in order to limit the progression or cause the regression of gastric precancerous changes.

Background Endoscopic mucosal resection (EMR) is simple and quick and has low complication rates. However, the disadvantage of local recurrence or remnant rate limits the use of this technique. We aimed to analyse the outcomes of conventional EMR and EMR with circumferential incision (CIEMR), a simplified modification of EMR, in the endoscopic treatment of rectal carcinoid tumours. Methods A total of 59 consecutive patients with rectal carcinoid tumours without regional lymph node enlargement confirmed by endoscopic ultrasonography were included in the study. These patients underwent endoscopic treatment from January 2009 to September 2011 and were randomly designated into CIEMR ( n  = 31) or EMR group ( n  = 28). En bloc resection rate, pathological complete resection rate, procedure time, complications and follow-up outcomes were analysed. Results The en bloc resection rate was not significantly different between the CIEMR and EMR groups (100% versus 96.55%, P  > 0.05). The pathological complete resection rate was higher in the CIEMR group than in the EMR group (96.7% versus 82.14%, P  < 0.05). The overall complication rate, delayed bleeding and procedure time were not significantly different between the two groups. No recurrence was observed in either the EMR or CIEMR group. Conclusions CIEMR optimises the procedure of EMR and simplifies the technique of endoscopic submucosal dissection; thus, it has a better histologically complete resection rate and more acceptable complication rate than EMR. Thus, CIEMR may be preferable to conventional EMR for resection of rectal carcinoid tumours less than 15 mm.

Dependence on exogenous serine means that tumour growth is restricted in mice on a low-serine diet; this effect on tumour growth can be amplified by antagonizing the antioxidant response. Exploring dietary restrictions in cancer therapy Tumours acquire different metabolic adaptations to foster accelerated growth. This can lead to their dependence on crucial nutrients for anabolism. It had been shown that some non-essential amino acids, including serine, are required for tumour growth in mice. This report explores the effect of serine deprivation in endogenous tumour mouse models, uncovering how different oncogenic adaptations lead tumours to rely on exogenous serine or upregulate its cellular synthesis. Dependence on exogenous serine renders tumours sensitive to serine-deprivation diets, and this effect on tumour growth can be amplified by antagonizing the anti-oxidant response. The authors take a step towards dissecting how the metabolic vulnerabilities of cancer may be explored therapeutically in the future. The non-essential amino acids serine and glycine are used in multiple anabolic processes that support cancer cell growth and proliferation (reviewed in ref. 1 ). While some cancer cells upregulate de novo serine synthesis 2 , 3 , 4 , many others rely on exogenous serine for optimal growth 5 , 6 , 7 . Restriction of dietary serine and glycine can reduce tumour growth in xenograft and allograft models 7 , 8 . Here we show that this observation translates into more clinically relevant autochthonous tumours in genetically engineered mouse models of intestinal cancer (driven by Apc inactivation) or lymphoma (driven by Myc activation). The increased survival following dietary restriction of serine and glycine in these models was further improved by antagonizing the anti-oxidant response. Disruption of mitochondrial oxidative phosphorylation (using biguanides) led to a complex response that could improve or impede the anti-tumour effect of serine and glycine starvation. Notably, Kras-driven mouse models of pancreatic and intestinal cancers were less responsive to depletion of serine and glycine, reflecting an ability of activated Kras to increase the expression of enzymes that are part of the serine synthesis pathway and thus promote de novo serine synthesis.

Background: Small bowel adenocarcinoma (SBA) is a rare malignancy that accounts for 1–2% of gastrointestinal tumours. We investigated the clinical characteristics, outcomes, and prognostic factors of primary SBA. Methods: We retrospectively analysed the characteristics and clinical courses of 205 SBA patients from 11 institutions in Japan between June 2002 and August 2013. Results: The primary tumour was in the duodenum and jejunum/ileum in 149 (72.7%) and 56 (27.3%) patients, respectively. Sixty-four patients (43.0%) with duodenal adenocarcinoma were asymptomatic and most cases were detected by oesophagogastroduodenoscopy (EGD), which was not specifically performed for the detection or surveillance of duodenal tumours. In contrast, 47 patients (83.9%) with jejunoileal carcinoma were symptomatic. The 3-year survival rate for stage 0/I, II, III, and IV cancers was 93.4%, 73.1%, 50.9%, and 15.1%, respectively. Multivariate analysis revealed performance status 3–4, high carcinoembryonic antigen, high lactate dehydrogenase (LDH), low albumin, symptomatic at diagnosis, and stage III/IV disease were independent factors for overall survival (OS). Ten patients (18.5%) with stage IV disease were treated with a combination of resection of primary tumour, local treatment of metastasis, and chemotherapy; this group had a median OS of 36.9 months. Conclusions: Although most SBA patients were diagnosed with symptomatic, advanced stage disease, some patients with duodenal carcinoma were detected in early stage by EGD. High LDH and symptomatic at diagnosis were identified as novel independent prognostic factors for OS. The prognosis of advanced SBA was poor, but combined modality therapy with local treatment of metastasis might prolong patient survival.